Method of treating hyperchlorhydria and/or associated conditions

ABSTRACT

A METHOD FOR PREVENTING THE SECRETION OF EXCESSIVE AMOUNTS OF HYDROCHLORIC ACID IN THE STOMACH OF HUMANS SUFFERING FROM HYPERCHLORHYDRIA AND/OR ASSOCIATED CONDITIONS BY ADMINISTERING AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA   1,1-DI(CH3-),3-R1,3-(R4-N(-R3)-CH2-CH(-R2)-CH2-)PHTHALAN   WHEREIN R1 REPRESENTS THE PHENYL OR THE CYANO GROUP, AND R2, R3 AND R4 REPRESENT HYDROGEN OR METHYL.

United States Patent ABSTRACT OF THE DISCLOSURE A method for preventing the secretion of excessive amounts of hydrochloric acid in the stomach of humans sulfering from hyperchlorhydria and/ or associated conditions, by administering an effective amount of a compound of the formula CH3 CH3 CHR wherein R represents the phenyl or the cyano group, and R R and R represent hydrogen or methyl.

This application is a continuation-in-part of my earlier application Ser. No. 826,657, filed May 21, 1969, now U.S. Pat. 3,629,445 issued *Dec. 21, 1971, and a division, of application Ser. No. 866,396, filed Oct. 14, 1969, now U.S. Pat. No. 3,670,088.

This invention relates to a method for preventing the secretion of excessive amounts of hydrochloric acid in the stomach of humans suffering from hyperchlorhydria and/ or associated conditions. Since the usual peptic ulcer is frequently accompanied by, or the result of, hyperchlorhydria, my method is especially useful in the treatment of peptic ulcers and associated abnormal conditions of the gastrointestinal tract.

I have found that the chemical compounds of the following formulae, either in their base forms, or in the form of their acid addition salts with pharmaceutically accept- 6 able acids, are particularly effective in preventing the excessive secretion of hydrochloric acid.

ice

The compounds may be represented by the following formulae CH3 CH CH3 CH3 CH3 CH3 A O S /\CH: v.

in which R represents the phenyl or the cyano group, and R R and R represent hydrogen or methyl; R represents hydrogen or methyl; and R represents hydrogen or methyl. The chemical names of the compounds represented by the above formulae are as shown below. Oompounds of Formula I are:

N,3,3-trimethyl-l-phenyl-l-phthalanpropylamine N,N,3,3-tetramethyl-l-phenyl-l-phthalanpropylamine 1-cyano-N,3,3-trimethyll-phthalanpropylamine 1-cyano-N,N,3,3-tetramethy1-1-phthalanpropylamine N,N,fl,3 ,3-pentamethyll-phenyl- 1 -phthalanpropylamine 3,3-dimethyl-l-pheny1-l-phthalanpropylamine Compounds of Formula II are:

N,3 3-trimethyll-phenyll-benzo [c] thiophenepropylamine N,N, 3 3-tetramethyl-1-phenyl-l-benzo [c] thiophenepropylamine Compounds of Formula III are:

N,3,3-trimethyl-l-phenyl-l-indanpropylamine N,N,3,3-tetramethyll-phenyll-indanpropylamine.

The compounds of Formula I have been described in a paper by P. V. Petersen et al., in Acta Pharmacol. et Toxicol, vol. 24, p. 121 (1966), in Belgian Pat. 678,035, published Sept. 19, 1966, and in South African Pat. 67/ 1261, published July 31, 1967. Methods for their preparation are also disclosed in the above patents.

The compounds of Formula II have been described by Carlsson et al. in Brit. J. Pharmacol., vol. 36, p. 18 (1969), and their methods of preparation are disclosed in Belgian Pat. 709,229, published July 11, 19-68.

The compounds of Formula III have been described in the paper by Petersen et al. cited above, and methods for their preparation are discolsed in Belgian Pat. 687,628, published Mar. 1, 1967 and in Netherlands Pat. 6704297, published Sept. 29, 1967.

The acid addition salts of the above compounds are prepared by reacting the base with either one equivalent or preferably an excess of the appropriate acid in an organic solvent, such as ether or an ethanol-ether mixture. These salts, when administered to humans, possess the same activity as the base itself, in preventing the secretion of excessive amounts of hydrochloric acid. For many purposes it is preferable to administer the salts rather than the base compound. Among the acid addition salts suitable for this purpose are salts such as the sulfate, phosphate, lactate, tartrate, maleate, citrate and hydrochloride. The hydrochloride salts are especially convenient. Both the base compounds themselves and the above acid addition salts have the distinct advantage of possessing a relatively low order of toxicity.

The compounds of Formulae I, II, and III and their acid addition salts with pharmaceutically acceptable acids may be administered to humans suffering from hyperchlorhydria or associated conditions, for the purpose of preventing secretion of excessive amounts of the hydrochloric acid in the stomach and gastrointestinal tract thereof, orally or parenterally. For many reasons oral administration is preferred.

The compounds are soluble in a wide variety of pharmaceutically acceptable solvents and may readily be made up in solvents for oral administration. They may also be prepared with suitable carriers to form tablets or capsules. Alternatively, they may be suspended in suitable suspending agents and administered in this form.

When any of the compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above or their acid addition salts with pharmaceutically acceptable acids are prepared for oral administration, they may, for example, be incorporated with the usual excipients or carriers, such as lactose, starch or sucrose, in the form of capsules or tablets containing from 10-50 mg. of the active ingredient per capsule or tablet. These pharmaceutical preparations may contain the usual coloring agents, preservatives or other usual ingredients. When liquid preparations are preferred for oral ingestion, the compounds or their acid addition salts, described above, may be dissolved or suspended in a suitable nontoxic carrier, such as, distilled water, aqueous alcohol, or a pharmaceutically acceptable oil. The concentration of the active agent is selected to provide a generally useful composition.

A typical composition for oral ingestion, for example, may be a solution, containing to 50 mg. of the compound of Formula I N,3,3-trimethyl-l-phenyl-l-phthalanpropylamine hydrochloride or the compound of Formula II N,3,3 trimethyl-l-phenyl-l-benzo[c]thiophenepropylamine hydrochloride per millilitre to distilled Water, rendered isotonic by the addition thereto of sodium chloride, sodium citrate or glucose. Similar compositions may also be prepared with the other compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above.

Such solutions or suspensions may also contain the usual preservatives, sweetening agents, and other agents which are present in conventional liquid pharmaceutical preparations.

For parenteral administration, N,3,3-trimethyl-1-pl1enyl-l-phthalanpropylamine or N,3,3-trimethyl-1-phenyllbenzo[c] thiophenepropylamine or their acid addition salts With pharmaceutically acceptable acids may be dissolved or suspended in suitable sterile liquid carriers such as distilled water or oils of synthetic, animal, petroleum or vegetable origin, for example, soybean oil, sesame oil, mineral oil or propylene glycol. The usual preservatives and other ingredients used for pharmaceutical preparations for parenteral dose may also be incorporated. The concentration of the active agent in these preparations for parenteral use is selected to provide a generally useful composition. A

. typical composition would ordinarily constitute from about 2 to 5% by Weight, of N,3,3-trimethyl-l-phenyl-lphthalanpropylamine hydrochloride or of N,3,3-trimethyll-phenyll-benzo [c] thiophenepropylamine hydrochloride in sesame oil with 1.5% benzyl alcohol as a preservative. Similar compositions may also be prepared with any of the other compounds listed above of Formulae I, II, and III,

in which R R R R R and R are as defined above.

When utilizing any of the compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above or their acid addition salts, described above, as agents for combatting or preventing hyperchlorhydria, and/or associated conditions, the total dose of active agent may range from approximately 0.1 mg. per kilogram of body weight to 10 mg. per kilogram of body weight, with a preferred dosage range of from 0.2 mg. to 2.0 mg. per kilogram body weight. Generally, a parenteral dose is administered once a day, whereas the daily oral dose is administered in three or four applications. Such doses are considered to be effective amounts when, following their administration, either the amounts of hydrochloric acid secreted within a specified period of time by the human being so treated are significantly reduced, or when the subjective symptoms complained of by said human beings are reported as having disappeared, or being ameliorated or reduced in severity following such treatment.

The effects of any of the compounds listed above of Formulae I, II and III in which R R R R R a d R are as defined above and their acid addition salts with pharmaceutically acceptable acids as agents for preventing hyperchlorhydria and inhibiting hydrochloric acid secretion may be demonstrated by the use of rats, more especially the Shay rat. The rat is the preferred experimental mammal for demonstrating the acitvity of agents eifecting gastric acid secretion and its has been widely used in experimental medicine for this purpose. For instance, on page 149 in Pathophysiology of Peptic Ulcer, published by McGill University Press, Montreal, Canada in 196 3, Skoryna states that many of the drugs now in use in human medicine for the treatment of peptic ulcer have been evaluated by the Shay rat method. It is recognized by skilled pharmacologists that results obtained in the Shay rat in the evaluation of gastric acid conditions are translatable to results that will be obtained when the same drug is administered to human beings. For the value of the Shay rat in experimental gastroenterology, see also the article by Shay et al. in Gastroenterology, vol. 26, p. 906, (1954). This animal is generally recognized as the preferred, or standard, animal for use experimentally in testing drugs used to inhibit gastric acid secretion.

More specifically, it has been demonstrated that when the compound of Formula I N,3,3-trimethyl-l-phenyl-lphthalanpropylamine or the compound of Formula II N,3,3-trimethyl-1-phenyl 1 benzo[c]thiophenepropylamine or their respective acid addition salts, preferably the above hydrochloride salts, are administered to shay rats in dosages of 0.625 miligram per kilogram of body Weight, reduction in the basal hydrochloric acid secretion to a value Within the range of 57 percent to 64 percent of control values results. When the compounds were administered to Shay rats in dosages of 1.25 milligrams per kilogram of body weight an observed reduction of basal hydrochloric acid secretion from 44 percent to 49 percent of control values occurred. Again, more specifical ly, the ability of N,3,3-trimethyl-l-phenyl l-phthalanpropylamine hydrochloride or of N,3,3-trimethyl-l-phenyl-l benzo[cJthiophenepropylamine hydrochloride to inhibit the secretion of hydrochloric acid and prevent ulcer formation in rats, was demonstrated exeprimentally in accordance with the method described by Brodie et al. in Proc. Soc. Exp. Biol. Med., vol. 113, p. 998 (1963), this method having been modified to some extent in accordance with the procedure of Senay et al. as described in vol. 124, p. 1221 (1967) of the same publication. In this modified procedure rats were injected intraperitoneally with pharmaceutical preparations containing the compound as active agent. The intraperitoneal administration of N,3,3-trimethy1-l-phenyl-l-phthalanpropylamine hydrochloride in dosages of 63:1.4 milligrams per kilo gram of body weight was found to protect 50 percent off the test animals from ulcer formation. Under the condi tions of this test, -100 percent of the=untreate ratss used as controls developed gastric lesions, consisting of one or several macroscopical erosions of the glandular mucosa, often accompanied by haemorrhage. Similar results were also obtained when similar doses of any of the other compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above were used.

In a comparison with the known compound atropine sulfate, which is presently utilized for preventing ulcer formation, while atropine sulfate was found to protect from 50 to 75 percent of the test animals when administered at dosages of 2 milligrams per kilogram of body weight, the typical undesirable anti-cholinergic effects of atropine were clearly observable in the rats to whom the atropine sulfate had been administered. As contrasted with these undesirable effects the administration of the compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above to the test animals in the dosages referred to above were found not to result in any observable undesirable side effects, side effects resulting from anti-cholinergic activity being conspicuously absent.

The following examples will illustrate this invention.

EXAMPLE 1 (a) N,3,3 trimethyl 1 phenyl-l-phthalanpropylamine hydrochloride or N,3,3 trimethyl 1 phenyl-1- benzo[c]thiophenepropylamine hydrochloride (20 g.) is dissolved in 980 ml. of distilled water, the chloride (20 g.) is dissolved in 980 ml. of distilled water, the solution is made isotonic by addition of sodium chloride or sodium citrate or glucose, a preservative such as 0.1 percent weight by volume of Methylparaban and 0.015 percent weight by volume of Propylparaban or 0.5 percent weight by volume of chlorbutanol is added, the solution is made up to 1000 ml. with distilled water, sterilized by autoclaving or sterile filtration, and filled into 2 ml. ampoules or vials, to make a solution for parenteral administration containing 20 mg./ ml. of the active ingredient.

(b) In the same manner, but using 50 g. of N,3,3-trimethyl 1 phenyl 1 benzo[c]thiophenepropylamine hydrochloride, a solution for l-phenyl-1-thiophthalanpropylamine hydrochloride, 2. solution for parenteral administration containing 50 mg./ml. of the active ingredient is obtained and is filled into 20 ml. ampoules or vials.

(c) N,3,3 trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride or N,3,3 trimethyl l-phenyl-lbenzo[c]thiophenepropylamine hydrochloride (20 g.) is suspended in 965 g. of sesame oil and 15 g. of benzyl alcohol by means of a mechanical blender. The suspension is filled into 2 ml. ampoules or vials. After autoclaving, a suspension containing 2% of the active ingredient by weight is obtained for parenteral administration.

(d) Again in the same manner, but using 0.225 g., 0.45 g., 2.5 g., 5.0 g., or 10.0 g. of N,3,3-trimethyl-1- phenyl 1 phthalanpropylamine hydrochloride or of N,3,3 trimethyl 1 phenyl 1 benzo[c]thiophenepropylamine hydrochloride alone, without additives or preservatives, solutions for parenteral or oral administration for pharmacological purposes containing 0.225 mg./ ml., 0.45 mg./ml., 2.5 mg./ml., 5.0 mg./ml., and 10.0 mg./ ml. of the active-ingredient are obtained, respectively.

Similar solutions or suspensions are also prepared with any of the other compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above.

EXAMPLE 2 (a) N,3,3 trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride or N,3,3 trimethyl l phenyl-1- benzo[c]thiophenepropylamine hydrochloride (50 g.) is mixed with 150 grams lactone, 44 grams starch, 4 grams magnesium stearate and 2 grams sucrose. The mixture is granulated with addition of a small amount of water,

dried and compressed into tablets weighing 250 mg. each, to make 1000 tablets containing 50 mg. each of the active ingredient.

(b) In the same manner, but using 10 g. of N,3,3-trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride or N,3,3 trimethyl 1 phenyl 1 benzo[c]thiophenepropylamine hydrochloride, 190 glactose, 44 g. starch, 4 g. magnesium stearate, and 2 g. sucrose, there are obtained 1000 tablets of 250 mg. weight each, such tablets containing 10 mg. each of the active ingredient.

(c) Again in the same manner, but using 25 g. of N,3,3 trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride or N,3,3 trimethyl 1 phenyl-l-benzo [c]thiophenepropylamine hydrochloride, 175 g. glactose, 44 g. starch, 4 g. magnesium stearate, and 2 g. of sucrose, there are obtained 1000 tablets of 250 mg. weight each, such tablets containing 25 mg. each of the active ingredient.

Similar tablets are also prepared containing any of the other compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above.

EXAMPLE 3 The inhibition of basal gastric acid secretory activity by N,3,3-trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride or by N,3,3 trimethyl 1 phenyl 1- benzo[c]thiophenepropylamine hydrochloride was determined by a modified method of Shay et a1. cited above. Charles River female albino rats (Canadian Breeding Laboratories; -190 g.) were caged individually 48 hours prior to treating. After the first 24 hours of food deprivation the animals were given access to 8% sucrose in 0.2% sodium chloride for 8 hours. Water was permitted ad libitum except during the 8 hours of sucrose. Three hours after the pyloric ligation the animals were anesthetized with ether and the amount of acid in the stomach determined by titration against 0.1 N sodium hydroxide in a direct reading pH meter to 7.0. There were 4-9 animals in each group.

When rats were subjected to the above procedure without treatment with N,3,3-trimethyl 1 phenyl-l-phthalanpropylamine hydrochloride or with N,3,3-trimethyl- 1-phenyl 1 benzo[c]thiophenepropylamine hydrochloride approximately 0.45 milliequivalent of hydrochloric acid were secreted per rat during a period of three hours (0.44i0.03 to 0.47:0.04 milliequivalent).

A solution of N,3,3 trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride containing 0.225 mg./ml. in sterile distilled water was prepared, according to the procedure described in Example 1(d), and the rats to be treated with N,3,3 trimethyl 1 phenyl 1 phthalanpropylamine hydrochloride were administered with 0.5 ml. each of the above solution, equivalent to a dosage level of 0.625 mg./kg. body weight. This administration was carried out immediately following pyloric ligation,

and the acid contents of the stomach were determined three hours later in the same manner as described above. It was found that 0.27:0.03 to 0.28:0.05 milliequivalents of hydrochloric acid had been secreted in the above three-hour period by the animals treated as above, corresponding to a reduction to 57-64 percent of control values.

In another experiment a solution containing 0.45 mg./ ml. of N,3,3 trimethyl 1-phenyl-l-phthalanpropylamine hydrochloride, was prepared as described in EX- ample 1(d), and the rats were injected intraperitoneally with 0.5 ml. of that solution each in the same manner as described above, equivalent to a dosage level of 1.25

mg/kg. body weight. It was found that 0.21:0.03 milliequivalents of hydrochloric acid had been secreted by the animals treated in the above manner during the standard three hour period, corresponding to a reduction of secretion of hydrochloric acid to 49 percent of control values.

Using the same experimental procedure described above, it may be shown that the administration of the remaining preparations described in Example 1 reduce the secretion of hydrochloric acid in the animals relative to control values.

Similar results were also obtained when similar dosages of N,3,3 trimethyl-l-phenyl-1-benzo[c]thiophenepropylamine hydrochloride or any of the other compounds listed above of Formulae I, II, and III in which R R R R R and R are as defined above were used.

EXAMPLE 4 Male albino rats of 170-190 g. body weight each were restrained in a plastic box equipped with bafiles so as to make movements of the animal impossible, and were kept at room temperature in this condition for 45 minutes. The were then exposed for 105 minutes to a temperature of 5 C. One hour later the rats were killed with ether and their stomachs removed. The stomachs were cut open along the longest curvature and were then unfolded for inspection. The results were evaluated visually in an all or none fashion based on the presence or the absence of lesions independent of their number and severity. Under those conditions 80-100 percent of the untreated rats used as controls developed gastric lesions, consisting of one or several macroscopical erosions of the glandular mucosa, often accompanied by haemorrhage.

When rats were injected intraperitoneally 45 minutes before the beginning of the above test with doses of the solutions of N,3,3 -trimethyl-l-phenyl-l-phthalanpropylamine hydrochloride described in Example 1(c) corresponding to 2.5 mg. per kilogram body weight, 88 percent of the rat thus treated showed gastric lesions as described above. When the same experiment was repeated with doses corresponding to 5.0 mg. per kilogram body weight, 50 percent of the rats thus treated showed the same type of gastric lesions. And when this same experiment was repeated with doses corresponding to 10.0 mg. per kilogram body Weight, 36 percent of the rats thus treated showed the same type of gastric lesions.

When the above results were statistically calculated by Probit Analysis, it was found that the effective dose of N,3,3 trimethyl l-phenyl-l-phthalanpropylamine hydrochloride protecting 50 percent of the rats (ED was 6.3i1.4 mg. per kilogram body weight, and that such doses caused no untoward effects whatsoever. Similar results were also obtained when similar doses of any of the other compounds listed above of Formulae I, II, and III, in which R R R R R and R are as defined above were used. Atropine in doses of 2 mg. per kilogram body weight was used in the above experiments as a standard control, and while the above amount of atropine protected about 50 percent of the animals, the toxic side effects of atropine were apparent.

wherein R represents the phenyl or the cyano group, and R R and R represent hydrogen or methyl, with the proviso that when R is phenyl and R is hydrogen, R and R are the same.

2. The method of preventing the secretion of excessive amounts of hydrochloric acid in the stomach of humans as claimed in claim 1 in which the effective amount of the compound to be administered is within the range of from 0.1 mg. to 10 mg. per kilogram body weight.

3. The method of claim 2 wherein the compound is N,N,3 ,3-tetramethyl-1-phenyll-phthalanpropylamine.

4. The method of claim 2 wherein the compound is lcyano-N,3,3-trimethyl-l-phthalanpropylamine.

5. The method of claim 2 wherein the compound is 1- cyano-N,N,3,3-tetramethyl-l-phthalanpropylamine.

References Cited UNITED STATES PATENTS 3,479,360 11/1969 Allais et a1. 260*-287 R 3,679,687 7/1972 Wasley 260-287R OTHER REFERENCES Achives Internationale de Pharmacodynamie et de Therapie, vol. 193, No. 2 (1971), pp. .340-356.

STANLEY I. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 424-275, 330 

